The importance of thyroid hormones (TH) in regulating metabolic processes in tissues of vertebrate animals, including humans, is well established. Inherent to this endocrine system is its ability to respond both acutely and chronically to internal and external challenges that otherwise might disrupt critical physiological processes. The types 1, 2 and 3 iodothyronine deiodinases (D1, D2 and D3), a family of selenoproteins that activate and inactivate TH in many tissues, are key components of the thyroid homeostatic system in that they allow for tissue-specific regulation of TH levels and also impact circulating TH concentrations. In both nutritional deprivation and severe illness, a suppression of serum TH and TSH levels occurs. Based on correlative studies, the deiodinases have been implicated as important mediators of this response by (i) impairing peripheral production of the most active TH - 3,5,3'-triiodothyronine (T3) (through suppression of D1 activity), (ii) enhancing peripheral inactivation of T3 and thyroxine (by activation of D3 activity) and/or (iii) altering feedback regulation by circulating TH (through localized activation of the D2 in the hypothalamus). However, this concept that the deiodinases are critical to the alterations in TH economy observed in nutritional deprivation and illness is based primarily on indirect evidence, and we suggest that many of the current concepts regarding the pathophysiology of these conditions are incorrect. Specifically, based on our preliminary data and a critical assessment of the literature, we put forth the heretical proposal that the D1 and D2 play little, if any role, in the abnormalities of TH homeostasis observed in fasting and the non-thyroidal illness syndrome (NTIS). Rather, we hypothesize that a combination of decreased secretion of TH by the thyroid gland, alterations in the flux of TH between serum and tissues, enhanced expression of the D3, and critical central factors that suppress TRH and TSH secretion, mediate the changes in TH homeostasis that occur in these conditions. We have created colonies of D1-, D2- and D3-deficient mice (D1KO, D2KO, D3KO) by homologous recombination, and by cross-breeding we have generated a D1/D2KO mouse devoid of all 5'-deiodinase activity. These mice will be used in experiments designed to test specific aspects of our hypothesis. Thus, we will determine the systemic and tissue-specific roles of the D1 and D2 and other factors in mediating the effects of fasting and non-thyroidal illness on TH homeostasis. We will also assess the importance of enhanced expression of the D3 in mediating the changes in TH homeostasis that occur in these conditions. Lastly, we will determine the functional significance of the NTIS and the systemic and tissue-specific roles of the D3 in response to myocardial infarction and peripheral ischemia. These studies will provide new and important insights into the mechanisms by which humans and other species adapt to the challenges of food deprivation and severe illness. Nutritional deprivation and severe systemic illness present significant, and at times life-threatening challenges to humans and other animal species. Such conditions prompt a complex systemic hormonal response designed to cope with the threat to health. The thyroid axis is intimately involved in regulating energy balance, heart activity, brain function and a host of other metabolic processes. Adaptation of this hormonal system to the stresses of fasting and illness is thus of critical importance. This project will define the mechanisms by which the thyroid axis responds to fasting and illness and the clinical consequences of this adaptation. Such knowledge should lead to an improved understanding of how the body reacts to stress and lead to better interventions in the treatment of malnutrition and for patients with life-threatening illness.